The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the invention.
The bacterial genus Streptomyces is an important natural source of many antibiotics, which include streptomycin, tetracycline, chloramphenicol, macrolides (e.g., erythromycin, carbomycin) and moenomycins (“moes”).
Moes are complex mixtures of phosphoglycolipid compounds produced by many Streptomyces strains as well as other Actinomycets. Streptomyces ederensis, Streptomyces geysiriensis, and Streptomyces bambergiensis (exemplary American Type Culture Collection deposits include ATCC15304, ATCC15303, ATCC13879, respectively) have all been shown to produce moes. See Wallhausser et al., 1965; Lindner et al., 1961. There have also been reports of an unidentified Actinomyces strain which produces compound AC326-alpha, a close relative of one of the moes in the mixture, moe A (He et at, 2000). Additionally, there are reports of Streptomyces strains producing compounds similar to moe A, however the exact chemical structure of these compounds has not yet been established (Weisenborn et al., 1967; Slusarchyk et at, 1969; Takahashi et al., 1970; Meyers et al., 1969).
Although the mixture of moes (e.g., the mixture produced by the strain Streptomyces ghanaensis) has not been thoroughly analyzed, it has been found to contain moe A (FIG. 1) and several other moes, including A12, C1, C3 and C4. Moes A12, C1, C3 and C4 have been shown to represent either shunt products or intermediates of common biosynthetic pathway operating in the producer strain. Additionally, compounds which are thought to be novel moes (Eichhorn, P. et al., 2005; Liu et al., 2003) have also been discovered.
The chemical structure for some moes (e.g., pholipomycin and AC326α) has been established, while the chemical nature of other members of the mixture (e.g., prasinomycins, macarbomycin, teichomycin A1, 11837RP, 8036RP (quebemycin), 19402RP, ensanchomycin, prenomycin) remains to be determined.
Moe A, a major component of the moe mixture, belongs to a unique family of phosphorus-containing secondary metabolites. Moe A is a pentasaccharide decorated with a C25 isoprene chain on one end and a chromophore on the other. The structure of moe A is shown below in Formula I:

Moe A is active against many bacterial strains and is the only antibiotic known to bind directly to and inhibit bacterial transglycosylase (“TG”), enzymes involved in peptidoglycan biosynthesis (FIG. 2). Because peptidoglycan biosynthesis is essential for bacterial survival, the inhibition of transglycosylase is an attractive and as-yet unexploited drug target. Moe A has potent antibiotic activity, with minimum inhibitory concentrations against many Gram positive organisms (“MICs”) in the range of 0.01 to 0.1 μg/mL (Chen L et al., 2003) or greater than 0.1 μg/mL. For example, moe A is an effective inhibitor of cell wall biosynthesis in Gram-positive cocci, including glycopeptide-resistant strains (Goldman, 2000).
It is assumed that the outer membrane of Gram-negative bacteria prevents moe A from reaching the enzymatic target; however, there are several studies showing selective toxicity of moe A and macarbomycin to Gram-negative bacteria carrying conjugative R-plasmids (Iyobe 1973; Ridel 2000). Additionally, some moe A producing Streptomyces strains and various strains not known to produce moe A (or structurally related compounds) are resistant to high concentrations of moe A. Therefore, some general and widely distributed resistance mechanism may exist which is not necessarily associated with moe A biosynthesis. Perhaps some Streptomyces transglycosylases are intrinsically resistant to moe A, or an unusually thick cell wall prevents moe A from reaching its target, or both. Additionally, or alternatively, by analogy to vancomycin resistance genes in S. coelicolor (Hong 2002), there could be a specific, as-yet unidentified moe A resistance gene or gene cluster in Streptomycetes.
The structure-activity relationships of moe A and its derivatives have been studied by Welzel and coworkers. For example, various domains involved in bioactivity and target interactions (Welzel, 1992) have been identified (labeled A through H) (FIG. 1). It has been shown that the C-E-F trisaccharide portion of moe retains inhibitory activity both in vitro and in vivo, while the E-F disaccharide shows activity only in vitro. The phospholipid moiety appears essential for in vivo activity, but the lipid chain can be manipulated to some extent (e.g., hydrogenation of the double bonds does not significantly alter activity). The lipid may be responsible either for anchoring moe to the cell membrane and/or interacting with hydrophobic regions of TGs. Moe analogs containing neryl chains have enzyme inhibitory activity but no biological activity. The carbamoyl group at C3′, the hydroxyl group at C4′, and the carboxamide entity at C5′ of the F ring, as well as the acetyl group at C2′ of the E ring, are all thought to define the moe pharmacophore (Ostash 2005). Unlike many other natural product antibiotics, moe does not contain structural elements of polyketide or non-ribosomal polypeptide origin. However, moes do contain a phosphoglycerate lipid moiety, a structural element not found in any other secondary metabolites. Moe A has been used as a growth promoter in animal feed under the trademark Flavomycin®.